Scientists find bad eye gene

Researchers looking at debilitating protein-lipid deposits in the eye may not have to search blindly for a cure much longer.

In the future, scientists studying such deposits — which contribute to age-related macular degeneration — may get a little help from a recent breakthrough. Yale researchers, with scientists from several other institutions, published their results identifying the main gene involved in AMD in the April issue of Science. By analyzing genetic sequences from people with and without AMD, researchers singled out a gene responsible for the disorder by identifying differences in base pairs, or single-nucleotide polymorphisms.

AMD is a disease that primarily afflicts Caucasians aged 65 or older and leads to loss of vision, said Josephine Hoh, a professor at the School of Epidemiology and Public Health. Hoh said the most severe form of the disease may lead to total blindness and is incurable.

“There is no treatment,” Hoh said. “Once you get the disease, you’re basically just waiting to become blind.”

Vision becomes blocked due to deposits of the compound drusen that form in the macula, the highly sensitive area in the center of the retina.

“The macula is very important for us to see, to read and to drive,” Hoh said. “Once you lose the macula, you basically lose sight.”

Hoh conducted statistical analyses of genetic data collected by the National Eye Institute. The researchers analyzed 120,000 base pairs in 96 individuals, Hoh said. Comparison of the data led to the discovery of the single-nucleotide polymorphism that characterizes the AMD gene.

Several genes, as well as environmental factors such as nutrition and smoking, contribute to AMD. The gene identified in the study is likely the main gene causing the disorder, said Jurg Ott, a professor at Rockefeller University who contributed to the research.

“The discovery from our paper is against the traditional information of thinking of the disease,” Hoh said.

Previously, many scientists had believed macular degeneration resulted from problems in angiogenesis, or growth of blood vessels. “We found that it is actually a problem of the immune system,” she said.

To identify the cause of the protein-lipid deposits, the researchers used a novel method to analyze the genetic information — both case and control — from reserves at the National Eye Institute. Analysis of these data revealed only a few SNPs, which represent a difference of one base pair between the case and control samples in the genetic information. This was the first use of the SNP method for study of this disease and the first such study to use the HapMap database of SNPs.

“We just happened to be successful right away,” Ott said. “It shows the power of this approach.”

Once researchers identified the particular SNP, the researchers narrowed the number of possible culprit genes from four to one with the aid of HapMap, a database of SNPs.

“The SNP is used to trace the location of the gene,” said Shrikant Mane, a biotechnology director in Yale’s Department of Molecular Biochemistry and Biophysics. “With a sufficient number of these landmarks we can identify the gene.”

The identified gene produces an abnormal protein in people with the disease due to the replacement of a single amino acid.

Hoh stressed that while the discovery will definitely further AMD research, the immediate clinical benefits of the research are uncertain. Diagnoses offer limited value without specific treatments available to treat the disease, she said, and labs continue to search for other AMD-related genes and pathways to solve this problem.

“There is still a long way to develop a treatment based on the discovery,” Hoh said. “[But] if you know the difference in the variants that lead to the biochemistry, the treatment might not be far away.”